WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Angioedema

Anaphylaxis and angioedema requiring hospitalization and
emergency medical treatment have occurred with the first or subsequent doses of
DETROL LA. In the event of difficulty in breathing, upper airway obstruction,
or fall in blood pressure, DETROL LA should be discontinued and appropriate
therapy promptly provided.

Urinary Retention

Administer DETROL LA Capsules with caution to patients with
clinically significant bladder outflow obstruction because of the risk of
urinary retention [seeCONTRAINDICATIONS].

Gastrointestinal Disorders

Administer DETROL LA with caution in patients with
gastrointestinal obstructive disorders because of the risk of gastric
retention.

DETROL LA, like other antimuscarinic drugs, may decrease
gastrointestinal motility and should be used with caution in patients with
conditions associated with decreased gastrointestinal motility (e.g.,
intestinal atony) [see CONTRAINDICATIONS].

Controlled Narrow-Angle Glaucoma

Central Nervous System Effects

Detrol LA is associated with anticholinergic central nervous
system (CNS) effects [see ADVERSE REACTIONS] including dizziness and
somnolence [see ADVERSE REACTIONS]. Patients should be monitored for
signs of anticholinergic CNS effects, particularly after beginning treatment or
increasing the dose. Advise patients not to drive or operate heavy machinery
until the drug's effects have been determined. If a patient experiences
anticholinergic CNS effects, dose reduction or drug discontinuation should be
considered.

Hepatic Impairment

The clearance of orally administered tolterodine immediate
release was substantially lower in cirrhotic patients than in the healthy
volunteers. For patients with mild to moderate hepatic impairment (Child-Pugh
Class A or B), the recommended dose for DETROL LA is 2 mg once daily. DETROL LA
is not recommended for use in patients with severe hepatic impairment
(Child-Pugh Class C) [see DOSAGE AND ADMINISTRATION and Use In
Specific Populations ].

Renal Impairment

Renal impairment can significantly alter the disposition of
tolterodine and its metabolites. The dose of DETROL LA should be reduced to 2
mg once daily in patients with severe renal impairment (CCr: 1030 mL/min).
Patients with CCr < 10 mL/min have not been studied and use of DETROL LA in
this population is not recommended [see DOSAGE AND ADMINISTRATION and Use
In Specific Populations].

Myasthenia Gravis

Administer DETROL LA with caution in patients with
myasthenia gravis, a disease characterized by decreased cholinergic activity at
the neuromuscular junction.

Use in Patients with Congenital or Acquired QT Prolongation

In a study of the effect of tolterodine immediate release
tablets on the QT interval [seeCLINICAL PHARMACOLOGY], the effect on
the QT interval appeared greater for 8 mg/day (two times the therapeutic dose)
compared to 4 mg/day and was more pronounced in CYP2D6 poor metabolizers (PM)
than extensive metabolizers (EMs). The effect of tolterodine 8 mg/day was not
as large as that observed after four days of therapeutic dosing with the active
control moxifloxacin. However, the confidence intervals overlapped.

These observations should be considered in clinical
decisions to prescribe DETROL LA to patients with a known history of QT
prolongation or to patients who are taking Class IA (e.g., quinidine,
procainamide) or Class III (e.g., amiodarone, sotalol) antiarrhythmic
medications. There has been no association of Torsade de Pointes in the
international post-marketing experience with DETROL or DETROL LA.

Patient Counseling Information

Information for Patients

Patients should be informed that
antimuscarinic agents such as DETROL LA may produce the following effects:
blurred vision, dizziness, or drowsiness. Patients should be advised to
exercise caution in decisions to engage in potentially dangerous activities until
the drug's effects have been determined.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with tolterodine were conducted in
mice and rats. At the maximum tolerated dose in mice (30 mg/kg/day), female
rats (20 mg/kg/day), and male rats (30 mg/kg/day), exposure margins were
approximately 6-9 times, 7 times, and 11 times the clinical exposure to the
pharmacologically active components of DETROL® LA (based on AUC of tolterodine
and its 5-HMT metabolite). At these exposure margins, no increase in tumors was
found in either mice or rats.

No mutagenic or genotoxic effects of tolterodine were
detected in a battery of in vitro tests, including bacterial mutation assays
(Ames test) in 4 strains of Salmonella typhimurium and in 2 strains of Escherichia
coli, a gene mutation assay in L5178Y mouse lymphoma cells, and chromosomal
aberration tests in human lymphocytes. Tolterodine was also negative in vivo in
the bone marrow micronucleus test in the mouse.

In female mice treated for 2 weeks before mating and during
gestation with 20 mg/kg/day (about 9-12 times the clinical exposure via AUC),
neither effects on reproductive performance or fertility were seen. In male
mice, a dose of 30 mg/kg/day did not induce any adverse effects on fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C

At approximately 9-12 times the clinical exposure to the
pharmacologically active components of DETROL® LA, no anomalies or
malformations were observed in mice (based on the AUC of tolterodine and its
5-HMT metabolite at a dose of 20 mg/kg/day). At 14-18 times the exposure (doses
of 30 to 40 mg/kg/day) in mice, tolterodine has been shown to be embryolethal and
reduce fetal weight, and increase the incidence of fetal abnormalities (cleft
palate, digital abnormalities, intra-abdominal hemorrhage, and various skeletal
abnormalities, primarily reduced ossification). Pregnant rabbits treated
subcutaneously at about 0.3 - 2.5 times the clinical exposure (dose of 0.8
mg/kg/day) did not show any embryotoxicity or teratogenicity. There are no
studies of tolterodine in pregnant women. Therefore, DETROL LA should be used
during pregnancy only if the potential benefit for the mother justifies the
potential risk to the fetus.

Nursing Mothers

Tolterodine is excreted into the milk in mice. Offspring of
female mice treated with tolterodine 20 mg/kg/day during the lactation period
had slightly reduced body weight gain. The offspring regained the weight during
the maturation phase.

It is not known whether tolterodine is excreted in human
milk; therefore, DETROL LA should not be administered during nursing. A
decision should be made whether to discontinue nursing or to discontinue DETROL
LA in nursing mothers.

Pediatric Use

Efficacy in the pediatric population has not been
demonstrated.

The pharmacokinetics of tolterodine extended release
capsules have been evaluated in pediatric patients ranging in age from 11–15
years. The dose-plasma concentration relationship was linear over the range of
doses assessed. Parent/metabolite ratios differed according to CYP2D6
metabolizer status [see CLINICAL PHARMACOLOGY]. CYP2D6 extensive
metabolizers had low serum concentrations of tolterodine and high
concentrations of the active metabolite 5-HMT, while poor metabolizers had high
concentrations of tolterodine and negligible active metabolite concentrations.

A total of 710 pediatric patients (486 on DETROL LA, 224 on
placebo) aged 5–10 with urinary frequency and urge incontinence were studied in
two randomized, placebo-controlled, double-blind, 12-week studies. The
percentage of patients with urinary tract infections was higher in patients
treated with DETROL LA (6.6%) compared to patients who received placebo (4.5%).
Aggressive, abnormal, and hyperactive behavior and attention disorders occurred
in 2.9% of children treated with DETROL LA compared to 0.9% of children treated
with placebo.

Geriatric Use

No overall differences in safety were observed between the
older and younger patients treated with tolterodine.

In multiple-dose studies in which tolterodine immediate
release 4 mg (2 mg bid) was administered, serum concentrations of tolterodine
and of 5-HMT were similar in healthy elderly volunteers (aged 64 through 80
years) and healthy young volunteers (aged less than 40 years). In another
clinical study, elderly volunteers (aged 71 through 81 years) were given
tolterodine immediate release 2 or 4 mg (1 or 2 mg bid). Mean serum
concentrations of tolterodine and 5-HMT in these elderly volunteers were
approximately 20% and 50% higher, respectively, than concentrations reported in
young healthy volunteers. However, no overall differences were observed in
safety between older and younger patients on tolterodine in the Phase 3,
12-week, controlled clinical studies; therefore, no tolterodine dosage
adjustment for elderly patients is recommended.

Renal Impairment

Renal impairment can significantly alter the disposition of
tolterodine immediate release and its metabolites. In a study conducted in
patients with creatinine clearance between 10 and 30 mL/min, tolterodine and
5-HMT levels were approximately 2–3 fold higher in patients with renal impairment
than in healthy volunteers. Exposure levels of other metabolites of tolterodine
(e.g., tolterodine acid, N-dealkylated tolterodine acid, Ndealkylated
tolterodine, and N-dealkylated hydroxy tolterodine) were significantly higher
(10–30 fold) in renally impaired patients as compared to the healthy
volunteers. The recommended dose for patients with severe renal impairment
(CCr: 10-30 mL/min) is DETROL LA 2 mg daily. Patients with CCr < 10 mL/min
have not been studied and use of DETROL LA in this population is not
recommended [see DOSAGE AND ADMINISTRATION and WARNINGS AND
PRECAUTIONS]. DETROL LA has not been studied in patients with mild to
moderate renal impairment [CCr 30-80 mL/min].

Hepatic Impairment

Liver impairment can significantly alter the disposition of
tolterodine immediate release. In a study of tolterodine immediate release
conducted in cirrhotic patients (Child-Pugh Class A and B), the elimination
half-life of tolterodine immediate release was longer in cirrhotic patients
(mean, 7.8 hours) than in healthy, young, and elderly volunteers (mean, 2 to 4
hours). The clearance of orally administered tolterodine immediate release was
substantially lower in cirrhotic patients (1.0 ± 1.7 L/h/kg) than in the
healthy volunteers (5.7 ± 3.8 L/h/kg). The recommended dose for patients with
mild to moderate hepatic impairment (Child-Pugh Class A or B) is DETROL LA 2 mg
once daily. DETROL LA is not recommended for use in patients with severe
hepatic impairment (Child-Pugh Class C) [see DOSAGE AND ADMINISTRATION and
WARNINGS AND PRECAUTIONS].

Gender

The pharmacokinetics of tolterodine immediate release and
5-HMT are not influenced by gender. Mean Cmax of tolterodine immediate release
(1.6 μg/L in males versus 2.2 μg/L in females) and the active 5-HMT
(2.2 μg/L in males versus 2.5 μg/L in females) are similar in males
and females who were administered tolterodine immediate release 2 mg. Mean AUC
values of tolterodine (6.7 μg·h/L in males versus 7.8 μg·h/L in
females) and 5-HMT (10 μg·h/L in males versus 11 μg·h/L in females)
are also similar. The elimination half-life of tolterodine immediate release
for both males and females is 2.4 hours, and the half-life of 5-HMT is 3.0
hours in females and 3.3 hours in males.

Race

Pharmacokinetic differences due to race have not been
established.

Last reviewed on RxList: 9/5/2012
This monograph has been modified to include the generic and brand name in many instances.